Amorphous engineered particle compositions of itraconazole (ITZ) and potential concentration enhancing polymers, cellulose acetate phthalate (CAP) and polyvinyl acetate phthalate (PVAP), were produced by ultra-rapid freezing to investigate the effect of these polymers on the bioavailability of ITZ solid dispersions. X-ray diffraction analyses of engineered particle compositions were shown to be amorphous. Modulated differential scanning calorimetry demonstrated that ITZ:CAP engineered particle compositions exhibited a strong correlation with the Gordon-Taylor relationship while ITZ:PVAP formulations exhibited positive deviations from predicted values attributed to hydrogen bonding interactions between the drug and polymer. Energy dispersive spectroscopy mapping demonstrated that the drug was homogenously distributed within all compositions, supporting the miscibility of the drug with the polymers. Scanning electron microscopy imaging of the particles demonstrated that the material existed in two general forms, discrete particles of approximately 5 microm and larger aggregates in excess of 30 microm, with engineered particle compositions having approximately 15 times higher measured specific surfaces areas compared to micronized ITZ. In vitro supersaturated dissolution results showed that all compositions provided significantly lower levels of supersaturation in acidic media and greater extents of supersaturation in neutral media compared to Sporanox pellets. ITZ: CAP formulations provided the greatest degree and extent of supersaturation in neutral media. Dissolution data were fitted to an exponential relationship based on a simplified model of particle growth, allowing for the determination of drug half-life in solution for evaluation of stabilization behavior. 1:2 ITZ:CAP showed superior in vitro performance compared to all other engineered particle compositions and was selected for in vivo testing. Although not fully elucidated, data indicated that the stabilization mechanism was due to interactions between the drug and polymer, primarily attributed to steric hindrance resulting from the molecular weight of the polymer chain and chemical composition of the polymer backbone relative to position of hydrogen bonding sites. In vivo testing conducted in Sprague-Dawley rats (n = 6) demonstrated a significant improvement in oral bioavailability from the 1:2 ITZ:CAP (AUC = 4,516 +/- 1,949 ng x h/mL) compared to the Sporanox pellets (AUC = 2,132 +/- 1,273 ng x h/mL) (p < or = 0.05). Additionally, the more rapid onset of action indicated superior targeting of the upper small intestines, and the prolonged half-life suggested the utility of CAP to maintain supersaturated concentrations, in vivo. These results demonstrated that amorphous compositions of ITZ and enteric concentration enhancing polymers provided improved bioavailability due to enhanced intestinal targeting and increased durations of supersaturation.

No abstract

The results of this study strongly suggest that substantial improvements in oral antifungal therapy with ITZ can be achieved via intestinal targeting and polymeric stabilization of supersaturation.

No abstract

The production of amorphous solid dispersions via hot melt extrusion (HME) relies on elevated temperature and prolonged residence time, which can result in potential degradation and decomposition of thermally sensitive components. Herein, the rheological properties of a physical mixture of polymer and an active pharmaceutical ingredient (API) were utilized to guide the selection of appropriate HME processing temperature. In the currently studied copovidone-nifedipine system, a critical temperature, which is substantially lower (∼13 °C) than the melting point of crystalline API, was captured during a temperature ramp examination and regarded as the critical point at which the API could molecularly dissolve into the polymer. Based on the identification of this critical point, various solid dispersions were prepared by HME processing below, at, and above the critical temperature (both below and above the melting temperature (T) of crystalline API). In addition, the resultant extrudates along with two control solid dispersions prepared by physical mixing and cryogenic milling were assessed by X-ray diffraction, differential scanning calorimetry, hot stage microscopy, rheology, and solid-state NMR. Physicochemical properties of resultant solid dispersions indicated that the identified critical temperature is sufficient for the polymer-API system to reach a molecular-level mixing, manifested by the transparent and smooth appearance of extrudates, the absence of API crystalline diffraction and melting peaks, dramatically decreased rheological properties, and significantly improved polymer-API miscibility. Once the critical temperature has been achieved, further raising the processing temperature only results in limited improvement of API dispersion, reflected by slightly reduced storage modulus and complex viscosity and limited improvement in miscibility.

These results showed that production of amorphous solid dispersions containing concentration-enhancing polymers through KinetiSol Dispersing can provide improved oral bioavailability; however, additional formulation techniques must be developed to minimize variability associated with natural variations in subject gastrointestinal physiology.

The impact of melt extrusion (HME) and spray drying (SD) on mechanical properties of hypromellose acetate succinate (HPMCAS), copovidone, and their formulated blends was studied and compared with that of reference excipients. Tensile strength (TS), compression pressure (CP), elastic modulus (E), and dynamic hardness (Hd ) were determined along with Hiestand indices using compacts prepared at a solid fraction of ∼0.85. HPMCAS and copovidone exhibited lower Hd , lower CP, and lower E than the reference excipients and moderate TS. HPMCAS was found to be highly brittle based on brittle fracture index values. The CP was 24% and 61% higher for HPMCAS after SD and HME, respectively, than for unprocessed material along with a higher Hd . Furthermore, the TS of HPMCAS and copovidone decreased upon HME. Upon blending melt-extruded HPMCAS with plastic materials such as microcrystalline cellulose, the TS increased. These results suggest that SD and HME could impact reworkability by reducing deformation of materials and in case of HME, likely by increasing density due to heating and shear stress in a screw extruder. A somewhat similar effect was observed for the dynamic binding index (BId ) of the excipients and formulated blends. Such data can be used to quantitate the impact of processing on mechanical properties of materials during tablet formulation development.

In this study, hot melt extrusion (HME) and KinetiSol Dispersing (KSD) were utilized to prepare dissolution-enhanced solid dispersions of Roche Research Compound A (ROA), a BCS class II drug. Preformulation characterization studies showed that ROA was chemically unstable at elevated temperatures and acidic pH values. Eudragit L100-55 and AQOAT LF (HPMCAS) were evaluated as carrier polymers. Dispersions were characterized for ROA recovery, crystallinity, homogeneity, and non-sink dissolution. Eudragit L100-55 dispersions prepared by HME required the use of micronized ROA and reduced residence times in order to become substantially amorphous. Compositions containing HPMCAS were also prepared by HME, but an amorphous dispersion could not be obtained. All HME compositions contained ROA-related impurities. KSD was investigated as a method to reduce the decomposition of ROA while rendering compositions amorphous. Substantially amorphous, plasticizer free compositions were processed successfully by KSD with significantly higher ROA recovery values and amorphous character than those achieved by HME. A near-infrared chemical imaging analysis was conducted on the solid dispersions as a measure of homogeneity. A statistical analysis showed similar levels of homogeneity in compositions containing Eudragit L100-55, while differences were observed in those containing HMPCAS. Non-sink dissolution analysis of all compositions showed rapid supersaturation after pH adjustment to approximately two to three times the equilibrium solubility of ROA, which was maintained for at least 24 h. The results of the study demonstrated that KSD is an effective method of forming dissolution-enhanced amorphous solid solutions in cases where HME is not a feasible technique.